JPS63270677A - Component for selective separation - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention is directed to the use of components useful for selective separation of amines (moi
ety), a separation compound bound to said component, and a membrane or liquid or solid containing said compound in polymeric form. The invention further relates to methods for producing the components and separation methods using the components, compounds or membranes.

BACKGROUND OF THE INVENTION Selective separation of amines is useful, for example, in the synthesis of some classes of drug molecules. Norcodine, a tertiary amine, can be synthesized from codine, a tertiary amine, i.e., N-methylnorcodine, but it is often difficult to carry out this reaction selectively with good yield by chemical methods. .

Norcodine and formaldehyde can be readily obtained by dealkylation of codine using Cunninghamella sp. microorganisms under fermentor conditions. In this case, however, analytical-scale HPLC can be used to effectively control this reaction, but when produced on a large scale, the chemical and physical properties of the products and reactants are similar. This makes separation difficult. Therefore, this separation problem must be solved in order to carry out this type of bioconversion on a commercial basis.

A known solution to this separation problem is molecular recognition (molec
This method is based on the fact that the receptor preferentially forms a complex with protonated norcodine. Among the various types of receptor molecules available, crown ethers, such as 1,4,7,
10.13,1.6-Hexaoxa-cyclooctadecane (i.e., 18-crown-6) forms a complex with the RNH, cation, and the smaller raun, diazo-12-crown-4 (i.e., 1 .7-Shioxer4.
It is known that 1O-diazo-cyclododecane) strongly binds to the R2NH, cation, but not to the R3NH cation. The ether is believed to be bound as shown in formula (I): Furthermore, since this receptor is easily derivatized, it can be coupled to a liquid polymer for continuous liquid-liquid extraction. It is proposed to develop a law. However, the inventors have discovered that binding to this receptor has been a major obstacle in developing this method and that other receptors, such as oxa analogues of said compounds, i.e. 12-crown-4-ether [1,4,7,10-
Tetraoxane clododecane] was found suitable and preferred; however, it is difficult to chemically modify 12-crown-4-ether since it is not directly bonded to the support.

Problems to be Solved by the Invention The present invention was made in order to solve the above-mentioned problems and provide a component useful for selective separation of amines.

Means for solving the problem, that is, the present invention, provides 1.4,7.10-tetraoxa-2
-Alkenyl-cyclododecane, 1,4,7゜1O11
Concerning 3-pentaoxa-2-alkenyl-cyclopentadecane and 1,4.7,10,13.16-hexaoxa-2-alkenyl-cyclooctadecane.

The invention also relates to corresponding alkenyl moieties for attachment to carriers, and also to carriers endowed with one or more alkylene-polyoxa-cycloalkane groups derived from the above-mentioned compounds. The group may be bonded to a silicon atom, and the silicon atom may be part of a siloxane or silica particle. Therefore, the present invention extends to siloxanes (usually polysiloxanes having three or more silicon atoms) having this component as a substituent. The substituted polysiloxane may be in membrane form. The alkenyl group may be C1-C6 alkenyl, or ω-alkenyl, such as 1-propen-3-yl or 1-hexen-〇-yl, and the double bond may be terminal. The alkenyl group may be substituted with alkyl or aryl.

Furthermore, according to the present invention, α, ω-
The 3,6-thioxaoctamethylene bridge is converted to an unsaturated 1,2 by using a substituted (e.g. halo-substituted, such as chloro-substituted) ethoxyethyl ether (e.g. 1°2-bis(2-chloroethoxy)ethane). -diol (e.g. 1.
1,2-diol (prepared by hydroxylation of the 1- and 2-positions of 7-octadiene) and then remove the remaining unsaturated bonds in order to attach the component to the carrier. A method of making an alkenylcycloalkane and an alkenyl component is provided, the method comprising liberating the alkenylcycloalkane and the alkenyl component. This ether can be represented by the formula: X CH2CH20CH2[(CHz)O(CL)]
nCH2Y (wherein X and Y represent the same or different substituents, and n represents the number of l, 2, or 3) This unsaturated bond is released using a reagent such as chloroplatinic acid. Alternatively, the component may be attached to a substrate, such as column packing beads (eg silica beads or beads of siloxane, usually polysiloxane having 3 or more silicon atoms). The substrate thus displaced may be in membrane form or may be a liquid or solid separate. Substituted carriers separate tertiary amines from tertiary amines,
For example, it may be used to separate norcodine from codin. Norcodine retained on substituted substrates can be eluted in greater than 95% yield by simply changing the pH.

As already mentioned, efficient downstream processing is a major challenge in many chemical and biochemical processes that are becoming increasingly complex from a commercial point of view. Liquid polymers functionalized with appropriately designed molecularly recognizable receptor groups can themselves serve as extractants for specific products.

Advantages of linear polysiloxanes include that the polymer itself is easily available (for example, dimethylsiloxane polymer is commercially available as a silicone fluid), low toxicity,
These include high thermal stability, high antioxidant properties, low vapor pressure, resistance to biodegradation, high flash points, and the water immiscibility of these materials. Furthermore, known chemical methods allow specific functions to be imparted in a reproducible and controlled manner, resulting in polymers of the type of formula (III), where L is (indicates a functional group)
: While the dimethylsiloxane group is hydrophobic, the methylalkylene-siloxane group can be made hydrophilic and by varying the ratio of Solvent miscibility, water miscibility and chemical stability may be modified. The introduction of specific ligand-binding groups allows these fluids to act as selective extractants for specific water-soluble substrates. These materials can therefore be considered the fluid equivalent of an affinity chromatography column; the active sites are bound to the polymer and are not lost to the aqueous phase.

By applying this method to liquid-liquid extraction and using polysiloxane functionalized with crown ether,
N-methylated drug molecules formed in bioconversion methods may be selectively extracted. This extraction can be performed, for example, using the following reaction equation (
Even during the progress of the reaction as shown in IV), the reaction can be carried out continuously in the reaction vessel: Hereinafter, the present invention will be explained with reference to Examples.

EXAMPLE Under acidic conditions, only the secondary amine salt is 12-crown-
4 [Compound (■) Strongly complexly bonded to 1. This provides the basis for an effective solvent extraction method in which the product of the bioconversion reaction (rV), i.e., protonated norcodine, is removed by extraction in a crown ether functionalized polysiloxane liquid medium.

Compound (n) does not bind directly to the support, and it is difficult to modify it chemically. The new process according to the invention provides novel compounds l which provide bound 12-crown-4 derivatives of polysiloxanes.

4.7.10-tetraoxa-2-(1-hexene-6
-yl)-cyclododecane (VI), the corresponding propenyl compound and 15-crown-5
and 18-crown-6: According to the invention, this compound can be easily prepared at low cost from inexpensive starting materials and can be bonded to a polysiloxane to form the aforementioned polymer (III). can be obtained (in this case, L indicates the crown).

The polymer (I[I) has a x:y ratio, i.e., woody MeS
Polymers with different water solubility were obtained by varying the ratio of hydrophobic Me, SiO units to i(OXCH2)n-crown units. X
The values of and y can be changed arbitrarily. Preferably, the value of y/(x+y+2) is between 2 and 10%, but the best effect is obtained when there are very few or very many functional groups. Preferably x+y is 1-1200, especially at least 3, more preferably at least 15, most preferably at least 28, such as at least 50.

Preferably X+Y is up to 1000, more preferably 50
up to 0, most preferably up to 100.

The polymer may be soluble or sticky when used as an aqueous extractant. The effect of changing the value of x+y can be partially compensated by changing the value of y/x in the same sense.

The following five types of polymers represented by the general formula (■) are (■a), (■b), (■C), (■d) and (■e
) was prepared: Me3SiO(Me2SiO)x(MeSiO)ySi
Me3 "Polymer (■a): x-3, y=5 It is unsuitable as an extractant because it is miscible with water.

Polymer (■b): x=46, y-2 Surprisingly, it is slightly soluble in water and therefore unsuitable as an extractant.

Polymer (■c): x-284, y=12 Hydrophobic and suitable for extraction involving aqueous media.

Polymer (■d): x=47, y=1 Shows properties similar to polymer (■C).

Polymer (■e): x=O1y-1 The method for producing the above polymer is as follows.

1,4,7.10-tetraoxa-2-(l-hexen-6-yl)-cyclododecane (Vl) is the following 2
It can be easily prepared in 18% yield by steps: (i) CH2=CH(CH2)mcH=cH, KMnO
+CH208CHOH(CH2)mct(=CHCH2
O8CHOH(CH2)[(CHz)so]n(CHz
)zc++CI(20HcHOH(CHz)mcH=c
In place of one or both of the H2-CQ substituents, C
Hx-paraphenylene-5O2 may also be used. Li+
acts as a template around which a crown of appropriate size is formed. n=2
In the case of n-3, it is appropriate to use Na'' used as NaOH, and in the case of n-3, elemental K is appropriate.

Chain by-products are the main volatiles and these are distilled off.

n months or 2, in step (i) use as little dimethyl sulfoxide as solvent and hold at 110 °C for at least 48 hours (when n = 3 use tetrahydrofuran) .

The 12-crown-4 functionalized polysiloxane (VT) was then attached to the 50 chain length polysiloxane (in this case no solvent was used).

(i) MesSiO(MesSiO)<a(IJe
H5iO)zsilJ e, + (Vl)Me,Si
O(Me, 5iO), , (MeSiO)2SiMe.

By repeating the above synthetic procedure with n as 2 and 3, CH2=C
H(CH,), -15-crown-5 and CH2-C
H(CH2)4 18-crown-6 was prepared. The alkenyl chain length was varied by varying the value of m.

Special code: When +n=1, the compound is CH2=CHCH
215-crown-5 is useful. These crown compounds were bonded to the linear polysiloxane component as in the case of compound (2b). These compounds are
It is useful for the selective complexation and extraction or transport of ionic metal ions of specific sizes.

By repeating this synthetic procedure with an insufficient amount of compound (Vl), excess MeH3iO groups remain;
The group may be crosslinked with other 51 groups by cleavage of the 5i-H bond, for example using a tin catalyst, to form a membrane, or it may be attached to a solid substrate, such as silica.

Crown ether derivatives (n), (V) and (Vl)
solution of piperidinium, N-methylpiperidinium,
Protonated norcodin or protonated codin (
(See reaction formula (■)) was investigated under various conditions.

Spectroscopic studies show that stable l:1 adducts result from strong complexation between the secondary amine salt and each crown ether derivative and can be isolated from both hydroxyl and non-hydroxyl solvents. There was found. The properties of these adducts have been fully elucidated, and the stretching mode (IR) of NH, and the chemical shift of the proton of NH, ('
The changes in H-NMR) showed that complex formation took place via this functional group in all cases. By subjecting the protonated amine complex of compound (V) to several times of recrystallization using a dichloromethane-cyclohexane mixed solvent, the amine is gradually lost until it becomes pure, resulting in crystalline protonated diazo-12-crown-4. Barchlorate was obtained as the final product.

Compounds (■
), at a typical concentration of 10-3 to 10-4 molar, only protonated norcodine is strongly complex-bonded;
Extracted from a clear equimolar mixture of codin and norcodine present as barchlorate salts (see Table 1)
.

Table 1 (1) After extraction using equal volumes of extractant and amine solution, measurement was performed by HPLC (however, in the case of polymer (■b), the volume ratio was set to 1=2).

(2) Recovered from the polymer in approximately 95% yield by extraction with a 2M solution of NaOH in methanol.

Norcodine was almost quantitatively recovered from norcodine-containing polymers by extraction with a methanol solution of NaOH.

Throughout these operations, the polymer (■) and the norcodine-containing polymer remained free-flowing fluids suitable for use in single or multi-stage extraction systems.

Most inorganic membranes consist of finely porous inorganic solids. Conversely, most synthetic polymer membranes are completely organic in nature and have limited stability at high temperatures and in organic solvents. It is advantageous to combine the ease of manufacture, synthetic versatility and low cost characteristic of organic membranes with the thermal stability, solvent resistance and chemical inertness characteristic of inorganic materials. Among the available materials with an inorganic backbone that are advantageous for use as polymer membranes, polysiloxane-RR'5i-0-
3iRR'-0-5iRR'-0 (R o and R' represent alkyl or aryl) is considered to be optimal in terms of availability (silicon raw material), stability, known chemical properties, etc. This is utilized in the present invention. Selective modification of a limited number of silicon atoms in polydimethylsiloxane should be a means of controlling both the permeability and selectivity of this type of material, but such modifications are not available for commercially available materials. It is extremely difficult to do so.

However, a wide range of methods for synthesizing organofunctional methylroxanes are known [Brisd.
on) and Watts, J. Chem.

Soc, Dalton Trans 1985, p. 2191]. The above-mentioned organofunctional siloxane (III) can be obtained by copolymerizing these substances with cyclic polydimethylsiloxane. In this case, the X:y ratio can be precisely adjusted, resulting in polymers with a wide range of chemical and physical properties. It is known that the mechanical properties and porosity of heteropolysiloxane membranes depend on the type and number of organic groups, the presence of inorganic additives and the preparation method used to synthesize the membrane.

These synthetic techniques can therefore be used to systematically modify highly permeable polydimethylsiloxanes to obtain siloxanes with desired tuning properties.

More generally, these siloxanes are used to produce (a) membranes for liquid extraction (where the siloxane is cross-linked to the membrane itself);
b) liquids, or (C) solids (the siloxane is adsorbed or cross-linked to the surface) may be prepared.

Claims (1)

[Claims] 1,1,4,7,10-tetraoxa-2-alkenyl-cyclododecane. 2,1,4,7,10,13-pentaoxa-2-alkenyl-cyclopentadecane. 3,1,4,7,10,13,16-hexaoxa-2
-alkenyl-cyclooctadecane. 4. A carrier which provides one or more alkylene-polyoxa-cycloalkane groups derived from the cycloalkane according to any one of claims 1 to 3. 5. The carrier according to claim 4, wherein said group is bonded to a silicon atom. 6. The carrier according to claim 5, wherein the silicon atom is a part of siloxane. 7. The carrier according to claim 5, wherein the silicon atoms are part of silica particles. 8. The two oxygen atoms of the unsaturated 1,2-diol can be expressed as: X-CH_2CH_2OCH_2[(CH_2)O(C
H_2)] nCH_2-Y (wherein X and Y represent the same or different substituents, and n represents a number of 1, 2 or 3), 3. The method for producing a cycloalkane according to any one of 3. 9. The two oxygen atoms of the unsaturated 1,2-diol can be expressed as: X-CH_2CH_2OCH_2[(CH_2)O(C
H_2)]nCH_2-Y (in the formula, X and Y represent the same or different substituents, and n represents a number of 1, 2, or 3), and the product is bonded to a compound represented by 8. A method for manufacturing a carrier according to any of claims 4 to 7, comprising bonding to a carrier substrate by opening. 10. A carrier produced by the method of claim 9. 11. A method for separating a secondary amine and a tertiary amine, comprising bringing the secondary amine and the tertiary amine into contact with the carrier according to any one of claims 4 to 7 and claim 10.